1. Field of the Invention
The present invention relates to a chemical method for the controlled release and delivery of biologically active substances to body fluids.
2. Brief Description of the Prior Art
The use of systems for the slow delivery of medications is known in the art. These systems have been suggested for a wide range of diseases where accurate control of the concentration of released agent is not necessarily critical.
Most "controlled-release" systems known to the prior art however (see e.g. Sears, U.S. Pat. No. 4,145,410, who shows drug release from capsules which are enzymatically labile) are incapable of releasing medication at intervals and concentrations which are in direct proportion to the amount of a metabolite present in the human body. The delivery or release of drug in these prior art systems is thus not literally "controlled", but is simply a slow release, independent of external or internal factors.
For example, although injectable insulin has been available for the treatment of diabetes mellitus for over fifty years, it is apparent that the simple replacement of the hormone is not sufficient to prevent the pathological sequelae associated with this disease. The development of these sequelae is believed to reflect an inability to provide exogenous insulin proportional to varying blood glucose concentrations experienced by the patient. To solve this problem several biological and bioengineering approaches to develop a more physiological insulin delivery system have been suggested.
Metas et al (Diabetes 25, 785 (1976)) describe the transplantation into a diabetic animal, of pancreatic tissue from a healthy animal. The transplanted tissue provides a ready source of insulin whose release is controlled primarily by the level of glucose in the blood. This approach has only succeeded with highly inbred strains of animals, however, since tissue rejection otherwise becomes a limiting factor. Obtaining sufficient quantities of acceptably pure islet tissue for future clinical applications also poses significant problems.
Chick (Science, 187, 847 (1975)) avoids the problem of tissue rejection by culturing pancreatic islets on the outside of semipermeable tube-shaped membranes, bundles of which are enclosed by a cylindrical shell. Blood flows through the inner tubes when the system is interposed into the circulation of an animal providing nutrients to the cells. Glucose and insulin pass across the membrane, while larger immunologically active substances remain inside. The use of cultured tissue however implies that the system is only viable for short periods of time. Mechanical problems, such as clogging of the inner tubes by blood also prevent its extensive use.
Soeldner et al (NIH publication No. 76-854 (1976), pp 267 describe a glucose sensitive electrode which utilizes immobilized glucose oxidase to produce electric current inversely proportional to the blood glucose level. Glucose oxidase is a very unstable enxyme in this system, and thus limits the use of such an electrode.
Colten et al (Transplantation and Clinical Immunology, X, 165-173, Amsterdam, 1978) discuss a system which would eventually include an electronic glucose sensor, an insulin reservoir and pump, and electronics connecting the two. If the sensor finds glucose levels rising, an appropriate amount of insulin would be pumped into the bloodsteam--automatically. This system utilizes a platinum electrode catalyst for oxidizing glucose in the sensor. This results in less specific electrodes which show interference with other metabolites and so cannot be used with reliability.
All of these prior art systems take into account the critical relationship between the blood glucose levels and insulin released, and thus attempt to provide the necessary feedback response which would allow the release of insulin to be controlled directly by the amount of blood sugar present at any particular time. However, the systems suffer from a general lack of reproducibility, long-term effectiveness and reliability. None of them have been put into extensive use because of this. A reliable feedback system which does not depend on the use of electrodes or transplanted tissue has not yet been developed. The use of such a simple internally controlled system would greatly expand the use of controlled-release medications. It would be particularly useful in the feedback controlled release of other hormones such as somatostatin, and of modified pharmacological compounds such as enzyme inhibitors and hypoglycemic agents.